7/01/2010 @ 10:20AM

The Light Fantastic

Psychiatrist and bioengineer Karl Deisseroth sees depressed patients at a Stanford University clinic every week. Often he has to try drug after drug before stumbling on to a combination that finally works. Some people need electroconvulsive therapy, which blasts their brain with current to jar them out of the blues, risking side effects like memory loss. For some patients nothing works.

The problem: Researchers don’t have the slightest idea which brain circuits cause depression. They can’t clearly map depression in an imaging machine, and there is no laboratory test for it. The inner workings of the brain are so opaque that “we don’t even have good theories for what might be going on” when people become hopeless or suicidal, Deisseroth says. The same holds true for other mental diseases like schizophrenia. “It is the least technologically advanced field of medicine in many ways,” he says.

When he isn’t seeing patients, Deisseroth, a mild-mannered 38-year-old with a mop of brown hair, spends his days in a bustling basement lab beneath Stanford’s James H. Clark Center for Biomedical Engineering & Studies in Palo Alto, Calif. He and 42 fellow researchers are pioneering a radical technology to shine a bright light on the cellular causes of mental illness. He uses an improbable combination of green algae, blue lasers, gene therapy and fiber optics to map neural circuits deep inside the brain with a precision that has never been possible before. He hopes this will help identify what goes awry to cause disorders like depression, anxiety, schizophrenia and autism.

The technique, dubbed optogenetics, is barely five years old and, so far, has been used only on laboratory animals. But brain scientists are already talking excitedly about how this will do for neuroscience what the telescope did for astronomy. “Basic questions that people have been asking for decades are going to be answered with these approaches,” says Michael Hausser, a neuroscientist at University College London. “It is difficult to overestimate the potential.” Adds Rutgers University neuroscientist György Buzsáki: “It is a fantastic revolution. If Karl doesn’t do anything else, if he just sits in his office, he will get a Nobel Prize–there is no question in my mind.”

Optogenetics could someday lead to implantable brain devices that correct malfunctioning circuits by zapping them with pulses of light. It might be able to selectively turn off brain cells that are overactive, as in epilepsy. In a $14.9 million project sponsored by the Pentagon, Deisseroth and collaborators at Stanford and Brown University are taking initial steps toward making a neural prosthesis for soldiers with brain or spinal injuries.

The technique begins with the placing of light-sensitive proteins from green algae inside specific types of brain cells. The cells can then be turned on or off with pulses of blue and yellow light. Currently researchers do this using fiber-optic cables hardwired into mouse brains, but they are working on wireless setups. In one experiment that Deisseroth shows to lab visitors, a pulse of light to the right side of a mouse’s motor cortex makes the animal run in circles to the left. In another experiment the researchers wake up sleeping mice by sending a light signal to the hypothalamus, the brain’s controller of sleep-wake cycles.

Scientists have long been hobbled by the lack of a good technology to explore how clusters of neurons coordinate their activity. They can record electrical signals from individual brain cells. Or they can look broadly at the whole brain using magnetic resonance imaging. There has been little in between. It is like trying to figure out how the U.S. economy works using only satellite photos and interviews with random people in the street.

This is where optogenetics may have a huge advantage. The viruses used to deliver the light-sensitive proteins can be engineered to target very specific clusters of brain cells. Researchers can then turn on and off just those brain cells in laboratory animals and see what happens.

After majoring in biochemistry at Harvard, Deisseroth got an M.D. and a neuroscience Ph.D. from Stanford and made his breakthrough almost immediately after starting his own lab in 2004, taking advantage of a 2002 discovery of light-sensitive proteins in green algae called channelrhodopsins. A blue light on the proteins opens a hole in the cell, allowing charged ions to flow in.

The idea that this algae protein might be used to control human cells was obvious, but there were all sorts of reasons that it might not work. “A lot of people thought about it, but nobody was crazy enough to try it,” recalls Deisseroth. “We were.” One key collaborator pushing it forward was Edward Boyden, who was then wrapping up his Ph.D. at Stanford. The idea of controlling brain cells with light “captured our imagination,” recalls Boyden, who now runs his own lab at MIT. A third researcher then in Deisseroth’s lab, Feng Zhang, helped engineer a virus to deliver the algae gene into brain cells. The long-shot experiment worked, they reported in Nature Neuroscience in 2005. Since then Deisseroth and Boyden have discovered other microbial proteins that can be used to turn brain cells off with light.

Today at least 600 university labs are furiously pursuing the technology, which Deisseroth and Boyden have freely shared. One blogger compared Deisseroth to a skier who has just set off an avalanche and is racing to stay ahead of it. He is keeping pace so far. Many scientists will never get a single study published in Science or Nature, the most prestigious scientific journals. In 2009 Deisseroth had three papers in Nature and two in Science. “Whenever he is not sleeping or eating, he is working,” recalls Zhang, now at Harvard.

Optogenetics could improve upon existing implanted devices that are used to treat Parkinson’s disease, obsessive-compulsive disorder and other ailments with pulses of electricity. An optogenetics device could hit more specific subsets of brain cells than those devices can. The medical-device giant Medtronic already has a small group working on a prototype device to see what would be needed to make optogenetics therapy possible. “It’s a disruptive technology,” says Timothy Denison, senior engineering manager in Medtronic’s neuromodulation division. Such therapies are years off. One hurdle is that existing optogenetics setups consume too much energy to fit in a reasonable-size device.

Whether or not optogenetics itself becomes a therapy, Deisseroth hopes he will help psychiatrists move beyond the simplistic concept that mental illness is caused by depressed levels of brain chemicals like serotonin and dopamine. This approach has led to drugs like Prozac. But the fixation on brain chemistry is stifling progress, he believes. It ignores the way the brain really works: as a high-speed data processor. “This idea that psychiatric diseases are due to altered levels of neurotransmitters can’t be the case,” says a frustrated Deisseroth. “Yet it is the dominant paradigm in psychiatry.”